Provoking the Immunotherapy Efficacy of Renal Medullary Carcinoma [RNA-seq II]

Renal medullary carcinoma (RMC) predominantly afflicts young individuals of African descent harboring sickle hemoglobinopathies such as sickle cell disease (SCD) or sickle cell anemia (SCA). RMC is refractory to targeted and immune therapy strategies used for other renal cell carcinomas. We have demonstrated that RMC is resistant to immune checkpoint inhibition despite harboring an inflamed tumor immune microenvironment. Hence, novel therapeutic strategies are urgently needed to reverse this resistance. We discovered that CD8+ T cells under SCD condition exhibit altered genomic architecture and ferroptosis, which significantly impairs the anti-tumor immunity of effector T cells. These observations may underscore a fundamental mechanism behind the distinct resistance of RMC resistance to immune checkpoint therapies. By leveraging the use of both mouse SCD model and humanized mice phenotypically representing SCD/SCA, as well as primary CD8+ T cells isolated from patients with SCA, we identified that the SLC7A11 gene is transcriptionally downregulated in the CD8+ T cells of SCA donors via genomic architecture alteration. The reduced expression of SLC7A11 partially accounts for the ferroptosis observed in the CD8+ T cells of SCD disease, via impairing the cystine transportation and synthesis of Glutathione (GSH). Our findings also demonstrated that treatment using a hydrogen sulfide slow-releasing donor restored the expression of SLC7A11, antagonized the ferroptosis of CD8+ T cells under SCD/SDA condition and restored anti-tumor immunity in vivo. Hence, our research findings provide novel mechanistic insights into SCD and RMC and pave the way to develop innovative therapeutic strategies to sensitize RMC to immune therapies.